Formulation of various pharmaceutical actives, especially lipophilic actives is a problem because many such actives are difficult to solubilize, by virtue of their poor solubility; because many formulations containing such actives have poor stability and hence are difficult to manufacture and in many instances require such formulations to be lyophilized or freeze dried; and because many formulations containing such actives are required to be formulated as emulsions and hence difficult to manufacture. This is especially true for formulations of such actives in the form of injectables, capsules, gargles, solutions etc and other dosage forms. Preparation of various lipophilic drugs that are poorly soluble or insoluble in water/other solvents in soluble pellucid has been a continuing problem in the art.
Examples of such pharmaceutical actives, useful in various physiological conditions to alleviate the pathology caused due to various disease conditions are the following, which are not restrictive and a person of skill in the art may select other compounds which fall into the aforementioned categories:    I) Steroids and Hormones;    II) Antimalarial agents;    III) Proton Pump Inhibitors;    IV) Analgesic Agents (NSAIDs and Narcotic Analgesics);    V) COX 2 Inhibitors;    VI) Hypnotic Agents;    VII) Antifungal Agents;    VIII) Oxicams;    IX) ACE Inhibitors;    X) Muscle Relaxants;    XI) Antibiotics;    XII) Aldosterone Receptor Antagonists;    XIII) Cardiovascular Agents;    XIV) Calcium Channel Blockers;    XV) Anti-arrhythmic Agents;    XVI) Cardiac Glycosides and other Drugs related to CVS;    XVII) Antipsychotic Agents;    XVIII) Anticonvulsants;    XIX) Diuretics;    XX) Anticancer Agents;    XXI) Immunosuppressants;    XXII) Vitamins and Minerals; and    XXIII) Peptides
In the past, numerous agents have been used to solubilize various categories of drugs. The use of organic solvents like Acetone, Methanol, Ethyl acetate, Tetrahydrofuran, Chloroform, Hexane, etc., for their subsequent use either as oral or injectable (intramuscularly or intravenously) is prohibited.
Use of oil and its derivatives has its limitations as these are derived from plant origin like sesame oil, cottonseed oil etc., which poses stability problems because their quality changes with season, may get unstable/rancid as well as their bulky viscous nature result in pain and further complication during application at the injecting site.
Manufacture of injectables using oil and its derivative also leads to problems from a quality control point of view. The tendencies of seasonal changes in oil quality (rancidity) and color change were problems encountered by manufacturing chemists. The pesticide residue from oil of natural origin is a potential risk factor for injectable forms. Further sterilization and difficulties during filtration are the added secondary problems.
Use of emulsions for solubilizing various drugs was also attempted. But the stability of emulsions, its particle size and sterility resulted in high cost of production. Moreover, various technologies are developed for administration in the injectable form and also pose the problems of pain at the site of the injection.
The abovementioned factors limit the use of oil as well as oil/water emulsions as solubilizing agents for the preparation of various categories of active drugs. Moreover, some of the derivatives of oil cause anaphylactic shocks and histamine release, thus reducing their usage.
The use of fatty acids and its derivative also requires special quality control and their therapeutic use in oral and injectable forms are therefore limited. Use of polyethylene glycol derivatives are quite high but there are limitations to their use as they can be administered up to certain levels only and are toxic at higher levels. Thus they become specific either for oral or local applications and their use is limited in injectables.
Further, the problems associated with oil-based injections are many, such as for instance a small test dose prior to actual administration is usually required to confirm tolerability of both active and oily vehicle; it causes pain, erythema and swelling at the site of injection; it leads to nodule formation at the site of injection; it is associated with a risk of damage to nerves, arteries or veins if improperly given or administered; if side effects occur they would be prolonged until plasma levels fall—hence the necessity for a test dose; it can take several weeks for plasma levels to reach steady state; injection technique competency, assessment and training are required; there are logistical difficulties for administering to a patient who is employed; there is a need for stabilizers and preservatives in larger amounts in such formulations for maintaining stability of the oily injections; some people have dislike or phobia of pain from the needles of such injectables; there could be staffing and medicine storage issues; it is viewed by some as stigmatizing and coercive, etc.
It is also found that there are some drugs available in the lyophilized form and the doctor/physician requires other pack of solvents to reconstitute before an administration. The technique of lyophilization is a costly process and unviable, leading many of such drugs uneconomical to patients.
Many drugs that are oil soluble have limited application as only to be administered intramuscularly and not used for ocular or intravenous purpose.
Complications associated with intramuscular injections are also many, such as they cause skin and tissue trauma; muscle fibrosis and contracture; nerve palsies, paralysis; anaphylactic shock; formation of thrombosis in veins; thrombo phlebitis; can involve infectious processes and cause abscesses or gangrene.
The formulation of drugs used for application as “Eye drops” in form of suspension/emulsions is limited because of their limited solubility in the aqueous media. Quality control attributes like stability, particulate matter, particle size etc., for such emulsions and suspensions, are the problems that are encountered by chemists during their preparation and application as “Eye drops”.
The problems associated with parenteral suspension formulations are also many, such as typically they limit the formulator in selecting the ingredients, which are parenterally acceptable as suspending agents, viscosity inducing agents, wetting agents and preservatives; they are difficult to manufacture—special facilities are required to maintain aseptic conditions for manufacturing such as crystallization, particle size reduction, wetting, sterilization etc.; stability of the formulations during the period between manufacture and use resulting in many occasions in settlement of solids, caking, causing difficulty in redispersion etc.; difficulty in maintenance of physical stability; non-uniformity of dose at the time of administration; vials to be shaken for uniformity prior to use; necessity of ensuring or ruling out of clumping or granular appearance of the suspension before withdrawing into syringes; after withdrawal, the injections are to be applied as soon as possible before its starts settling in the syringe, with the result that the entire problems can be an issue for the doctor/physician.
Many drugs for solubilization require milling or micronization to enhance the solubility in the solubilising agents. For instance, steroids require micronisation to solubilise in oil or its derivatives or in a co-solvent. The use of co-solvents or other additives in oil type product adds up difficulty in administration due to viscosity and may also cause hemolysis if not used in appropriate acceptable concentration in the body particularly for the parenteral preparation.
Thus the formulation of a clear solution of drugs for therapy has always been challenge with the need of a solubilizer to give clear solution.
It is known that ethanol is often used in varying amounts upto 50-60% for solubilization of many drugs during their preparation. However, if it is used for therapeutic application in the concentration through intravenous, intramuscular or for oral delivery, then it may lead to intoxication leading to its restrictions.
The use of Propylene Glycol is also limited. The safety regarding its parenteral application is only up to 40%, that too also through Intramuscular route and is considered as hemolytic and toxic at higher concentration to the central nervous system. The formulation containing 30% Propylene Glycol which has been used is known to cause hemolysis in humans. Hemolysis, CNS depression, hyperosmolality, and lactic acidosis have been reported after I.V. administration of Propylene glycol [NTP-CERHR Monograph on the Potential Human Reproductive and Developmental Effects of Propylene Glycol (March 2004) NIH Pub. No. 04-4482 Page II-30] Propylene glycol is viscous with a viscosity of 58.1 cps, thus limiting their use in IM/IV formulation and is not known for the Intravenous administration. (Handbook of Pharmaceutical Excipients, 3rd Edition by Dr. Arthur H. Kibbe, Page No. 443)
Cyclodextrins and its advanced derivatives are used in the formulation for solubilizing by the process of complexation of lipophilic compounds. Because of its toxicity, their use is limited. When administered, it is un-metabolized and accumulates in kidney as the insoluble cholesterol complexes resulting in severe nephrotoxicity and hence it has been used primarily for oral purpose. Questions always arise on safety when Cyclodextrin derivatives are administered parenterally (Handbook of Pharmaceutical Excipients, 3rd Edition by Dr. Arthur H. Kibbe, Page No. 165). Also the molecular weight of β-cyclodextrin is more than 1000 and hence after administration it could lead to problems of excretion with or without causing damages to kidney or any functions of the organ in the body.
Glycofurol is cyclic glycol derivative used nowadays as solubiliser solvent in parenteral products for intravenous or intramuscular injection in concentration up to 50% v/v. It has viscosity of 8-18 Cps which may also attribute to cloudiness when miscible in water. It is irritant when used undiluted; its tolerability is approximately the same as propylene glycol. Glycofurol has found to have effect on liver function. (Handbook of Pharmaceutical Excipients, Raymond C. Rowe, 5th Edition Page. No. 313). Central nervous system toxicity was also observed when given by intravenous (I.V.) injection. Necrosis of tissue was even observed when it was given intramuscularly (I.M.)
Chremophor El® (Trademark for a polyoxy-ethylene castor oil derivative), a surfactant was also used to solubilize poorly soluble drugs, which was found to have acute anaphylactoid reaction after initiation of intravenous fusion. It was a result due to improper mixing of this vehicle in parenterals and hence different mixing techniques were used to assess their effect on the distribution of Chremophor EL in the solution. This led to problem in parenteral formulation of various actives with this solubilizer and time is required for developing a proper technique for mixing of this solubilizer which limits its use in parenterals with non-safe toxic profile. Due to safety issues, it is used carefully as exceptional use and last resort as drug solubilising agent (eg. Pacltaxel injection, where balance of convenience suggests its use for terminal therapy of cancer verses anaphylaxis).
Ethyl oleate/Oleic acid ethyl ester is used nowadays for lipophilic compounds and for steroids as vehicle in certain parenteral preparations intended for intramuscular and subcutaneous administration. It is an oily liquid with viscosity of 3.9 Cps at 25° C., less viscous than fixed oils. It is found that it remains clear at 5° C., but darkens in color on standing, so antioxidants are to be added frequently to extend shelf life. Thus addition of group of antioxidants as well as use of amber bottle is required to protect it from light. This increases the cost of formulation by taking control on above factor of packing, stability (Handbook of Pharmaceutical Excipients, Raymond C. Rowe, 5th Edition Page. No. 274).
U.S. Pat. No. 4,628,053 relates to stabilized injection solutions of Piroxicam in which propylene glycol, ethanol and water as the solvent for parenteral administration, which might be viscous and painful at the site of injection.
U.S. Pat. No. 4,824,841 relates to a process for the transformation of Piroxicam into an hydrated form suitable for Oral, topic or parenteral administration.
U.S. Pat. No. 4,942,167 discloses aqueous pharmaceutical formulation containing lyophilized Piroxicam in Glycine as vehicle which is not transparent solution and stability can be issue.
U.S. Pat. No. 5,420,124A relates to an injectable Piroxicam potassium composition which contains triethyleneglycol as a solvent and stabilizer.
WO/1996/041646 disclose a pharmaceutical composition in the form of an aqueous solution or in the form of a product for reconstitution as an aqueous solution, for parenteral administration or ophthalmic administration, comprising Lornoxicam or a pharmaceutically acceptable salt thereof and a cyclodextrin selected from the group consisting of hydroxypropylated or sulphoalkylated derivatives of alpha, beta or gamma cyclodextrin.
Chinese Patent No. CN 101327193 relates to Lornoxicam freeze-dried powder injection and a preparation method thereof. The freeze-dried powder injection comprises Lornoxicam, mannite, tromethamine, EDTA and pH regulator.
From all the above limitations, it is apparent that there is need for a solvent, which is safe and non-toxic, which can be employed as a vehicle for preparation of pharmaceutical compositions in an efficient way through an economical process and being beneficial in treating mammals.
The present inventors have surprisingly found that most, if not all of the limitations/problems/concerns associated with the conventional formulations of various pharmaceutical actives, especially lipophilic actives can be overcome by employing Diethylene glycol monoethyl ether or other alkyl derivatives thereof as a primary vehicle or as a solvent in formulation of pharmaceutical compositions containing such pharmaceutical actives. Diethylene glycol monoethyl ether or other alkyl derivatives thereof are versatile enough to be accepted as vehicles for use in various drug delivery systems. It has been tested for its safety and toxicity and is reported to be safe for its therapeutic use through various routes of administration. Presently the ethyl derivative is in vogue, but use of methyl or any other alkyl derivatives may also be used.
The structure of Diethylene glycol monoethylether is as given below:

It is less viscous and safe. It has inherent viscosity of about 3.11 cps. It is soluble in water. The density of Diethylene glycol monoethyl ether is 0.985 to 0.991. Diethylene glycol monoethyl ether is less dense than water thereby making it easily flowable. As the compound has less viscosity it can be used for preparations of compositions which are having an easy syringability and thus advantageous to withdraw from vials or ampoules by the healthworkers. Further the same advantage offers doctors with its less painful impact and also less volume of liquid could be administered for the drug products in the therapeutic concentration through parenteral routes.
U.S. Pat. No. 5,837,714 discloses solid pharmaceutical dispersions comprising a poorly soluble drug substance, as SR48692 or Naproxen, Xylitol and Diethylene glycol monoethyl ether, and a method of preparing such dispersions comprising the steps of dissolving the poorly soluble drug substance in Diethylene glycol monoethyl ether and adding the solution to Xylitol. The dispersions exhibit good pharmaceutical properties and reduced levels of impurities and degradation products.
U.S. Patent Application No. 20100056982A1 teaches the photodynamic treatment of acne vulgaris. The method involves the topical administration of a photosensitizer composition comprising hydrophobic green porphyrins such as Lemuteporfin, Polyethylene glycol and skin penetration enhancers such as Oleyl alcohol and Transcutol™ to acne-affected skin and subsequent exposure of that skin to energy of a wavelength of activating the photosensitizer.
U.S. Patent Application No. 20100010059A1 teaches partially based on a discovery that an oral formulation containing N-(3-methylisothiazol-5-yl)-2-[1-(3-methylisoxazol-5-ylmethyl)-1H-indol-3-yl]-2-oxoacetamide unexpectedly enhances the oral bioavailability of the compound. In one aspect, this invention features an anticancer formulation, which contains d-alpha-Tocopheryl Polyethylene glycol 1000 succinate (“TPGS”), 2-(2-ethoxyethoxy)ethanol (“Transcutol”); and an effective amount of a compound of formula
WO 97/03698 teaches for Transdermal therapeutic system (TTS) having a backing film, having an acrylate-based pressure sensitive adhesive having a hormone content and a content of absorption accelerators and having a protective film, wherein the hormone content is provided by a content of an oestrogen and/or gestagen and/or androgen, and wherein the absorption accelerators are the two substances Oleic acid and 2-(2-ethoxyethoxy)-ethanol.
U.S. Pat. No. 5,552,153 teaches a pharmaceutical composition for transdermal delivery comprising an effective amount of an active ingredient selected from a Benzodiazepine and a Benzodiazepine antagonist; Ethanol; Caprylic acid; and Oleic acid. Additionally, the composition may contain Silicon fluid, Benzyl alcohol, and Diethylene glycol monoethyl ether or Dimethyl sulfoxide.
U.S. Pat. No. 5,998,392 teaches about the improved compositions of Benzoyl peroxide and methods of processing Benzoyl peroxide. More particularly, the invention relates to the use of a composition such as Transcutol®. Diethylene glycol monoethyl ether as a processing aid for making a new benzoyl peroxide premixture which can be admixed with an aqueous medium to make a new benzoyl peroxide flocculent composition.
U.S. Pat. No. 5,741,512 teaches with the Pharmaceutical compositions comprising Cyclosporin, e.g. Cyclosporin as “microemulsion pre-concentrate” and microemulsion form. The compositions typically comprise a C.sub.1-5 alkyl or tetrahydrofurfuryl di- or partial-ether of a low molecular weight mono- or poly-oxy-alkane diol, e.g. Transcutol or Glycofurol, as hydrophilic component. Compositions are also provided comprising a cyclosporin and, suitably, also a saccharide monoester, e.g. raffinose or saccharose monolaurate. Dosage forms include topical formulations and, in particular, oral dosage forms.